Subject: Immunotherapy; Ampligen; Drug-Approval Delays Date: Oct 21 1988 (571 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS issue #67, October 21, 1988. CONTENTS: [***** appears here at each new item] Passive Immunotherapy: Effective Treatment for Advanced AIDS? Ampligen: Study Stopped after Poor Results FDA Issues Rules to Speed Drug Testing Beyond an Unreasonable Doubt: Comments on Drug-Approval Delays ***** Passive Immunotherapy: Effective Treatment for Advanced AIDS? by John S. James In a study described last June at the Stockholm AIDS confer- ence and published last month in The Lancet , researchers treated six persons with advanced AIDS by transfusing blood plasma from donors who were healthy seropositives selected for having a high level of the antibody against the p24 protein of the AIDS virus. The patients had no detectable antibody to p24 before the treat- ment. But after a single treatment, these patients had the anti- body for several weeks -- the length of time depending on how much plasma they were given -- and showed impressive clinical as well as laboratory improvements. For example, there were ten opportunistic infections among the six patients in the two-month period before treatment, but only one in the two months the treatment was in effect. This treatment possibility, which is still unproven and not yet in use, is important because it might save lives which could not be saved by any other known means. And technically it would be easy to set up; the only possible obstacle is red tape. Com- munity organizing and support for such an effort may be neces- sary. The study is also important because it strongly indicates that persons with even advanced AIDS can recover, if the disease process can be stopped. How the Study Was Done We will only outline the procedure used because those who need more information can obtain the paper (Jackson and others, 1988 -- see References). First the researchers selected two donors who were HIV posi- tive and had very high levels of antibodies to p24 (see "Back- ground" section, below). Then they used plasmapheresis, a rou- tine procedure in blood banks, which separates plasma from cells in the blood, allowing the cells to be returned to the donor. (Plasmapheresis is used in blood banking because donors can replace plasma much more rapidly than cells, allowing more fre- quent donation, and the plasma itself is often all that is needed for transfusions or for making blood products. Also, plasma usu- ally does not need to be separated by blood type, as whole blood does.) Then the plasma was frozen and thawed, to rupture any remaining cells, and heat treated to kill any virus. Varying amounts of this treated plasma were infused intravenously into the recipients. These six patients were severely ill. For example, in the two months before the treatment, five of the six had pneumo- cystis, and altogether there were ten opportunistic infections. During two months after treatment, there was only one new infec- tion -- a fatal case of pneumonia in one patient who had liver disfunction and other complications before the infusion was given, and who did not benefit from the treatment. But after the treatment was discontinued (as part of the experimental design) and after the infused antibodies had disappeared there were nine opportunistic infections among the patients in a two-month period. Other improvements during treatment included weight gain, improved Karnofsky score (a rating of overall health), increased T-helper cells as well as T-8 and T-11 cells, and an immediate disappearance of P24 antigen after infusion of the anti-P24 antibodies. The one test which did not improve was skin sensitivity to antigens. Before the treatment, viral cultures from the plasma of four of the six patients had been positive. While the treatment was in effect, only one of 36 plasma cultures done was positive. After the treatment period, when the infused antibodies had disappeared, all of nine plasma cultures which were done were positive again. This difference is statistically significant -- as was the reduction in opportunistic infections. Since according to the study design the treatment was not repeated, even if successful, no long-term data was obtained. The treatment proved harmless, however, and there was no indication of viral resistance developing, suggesting that long-term use should be possible. Background Previous studies had shown that patients with a high level of antibodies against p24 or p17, which are core proteins of the AIDS virus, usually remained healthy. These and other observa- tions suggested a model of AIDS progression which has become widely known and accepted. In this model, antibodies to surface proteins of HIV, such as gp120, remain high in patients regardless of whether they do well or not. These antibodies do not tend to neutralize or inhi- bit the virus. But antibodies to core proteins of HIV, such as p24, are important indicators. These develop a short time after infec- tion. While they remain high, the person remains a healthy sero- positive. But eventually, for unknown reasons, most patients lose their ability to produce these antibodies, and the level falls to zero, or at least so low that it is undetectable. Then over the next several months, the patient is likely to develop p24 antigenemia, meaning that the p24 viral protein can be detected in the blood. This is what the p24 antigen test measures. (Do not confuse the p24 antigen test, which measures a protein pro- duced by the AIDS virus, with the test for the antibody against the p24 antigen. You want the antigen to be negative, and the antibody against the antigen to be high. The test for the anti- p24 antibody is not widely available, however.) Patients with high levels of p24 antigen are more likely to progress to ARC or AIDS during the following months or years. However, some patients with AIDS do not show the p24 antigen. One study of 57 patients suggested that lack of anti-p24 antibody might be an earlier indicator of risk of progressing to AIDS than the p24 antigen itself, or tests in common use such as T-helper count (Forster and others, 1988). Loss of anti-p24 antibody could precede AIDS by as much as 40 months. We have not yet obtained this paper, only an abstract, so we do not know if any of the 57 patients progressed to AIDS despite having the antibody, or if any remained healthy for a long time without it. Yet despite the clear fact that lack of anti-p24 antibody was associated with a greater risk of AIDS, it was still not clear that providing this antibody to patients who had lost the ability to make it would be helpful. In fact, during the ques- tioning session after the Stockholm talk by Dr. Jackson, a talk attended by leading AIDS researchers from such institutions as Johns Hopkins, Harvard, and the University of California San Francisco Medical Center, questioners were impressed but also surprised the clinical improvement. Questioners expected the immediate disappearance of p24 after infusion of the antibody -- which was observed -- but did not expect antiviral activity. In most studies, antibodies to HIV had failed to neutralize (inhi- bit) it. Dr. Jackson pointed out that some posters being presented at the Stockholm conference had shown that there was at least one site on p24 where an antibody would be neutralizing, although there were other sites where it would not be. In other words, antibody to p24 could have an antiviral effect, although until recently many experts would not have expected it. Technical Issues We asked Lisa Bero, Ph.D., a pharmacologist now with the Institute for Health Policy Studies who has several years experi- ence in drug development and has worked extensively with antibo- dies, to comment on possible technical problems with this treat- ment. She was concerned that the freezing and heating required to kill the virus might damage the antibodies. While the process seemed to work in the experiment reported, it might not work con- sistently. Other ways might work better to kill any virus in the plasma. There are standard methods (used in preparing gamma glo- bulin) which can separate antibodies in blood without danger of the product transmitting HIV. Some tests for the antibody level in the patients treated with the plasma could detect antibodies even if their structure had been damaged by the heat. The particular test (EIA) used by Dr. Jackson's team was a good choice, because it is less likely than others to make this error. Another possible problem is that patients might develop antibodies against the injected antibodies. This could cause "serum sickness", as well as making injected antibodies ineffec- tive. No sign of such a problem has been observed, however. Practical Considerations How long does each treatment with the plasma containing anti-p24 antibodies last? In the study by Dr. Jackson and oth- ers, the protective antibodies stayed in the blood from 30 to 70 days, depending on the amount given. With 50 ml of the plasma, antibodies of the recipient would last for about 30 days; with 500 ml, they would last about 70. The data suggested that as little as 5 ml might be effective. These numbers suggest that one healthy seropositive donor could provide antibodies to maintain at least several people with AIDS, or people at high risk of developing AIDS due to loss of their anti-p24 antibodies. The treatment did not harm any of the recipients. But pre- cautions were taken, such as observing the patients in the blood bank for one to two hours after the plasma infusion, and then releasing them with an accompanying person. Would donating protective antibodies be harmful to the donor? It seems unlikely. Six weeks after plasma donation, both donors had antibody levels twice as high as when they donated. In fact, there is substantial evidence that plasmapheresis (the plasma donation) itself can be beneficial to some persons with AIDS, apparently by lowering the level of harmful substances which otherwise accumulate in the blood. The Next Steps We do not know of anyone who is using this passive immunoth- erapy treatment now. Nor could we find anyone by press time who understood how this treatment could fit into the regulatory pro- cess and be made available quickly to patients. One activist described what was needed at this time as "breaking the ice"; that is, persons and organizations will have to pioneer and explore options for how the treatment might be made available. Technically, it would be easy to do. However, private- practice physicians would probably need the cooperation of a blood bank or clinic to do the plasmapheresis and heat treatment of the plasma. They would also need to consult with medical spe- cialists who were up to date on the research. And someone would need to find plasma donors who had high levels of appropriate antibodies. Two things should be done. We need more research to confirm that the treatment really does work -- and to help physicians know how to use it most effectively. Pharmaceutical companies, or community-based research organizations such as the Community Research Initiative, or the U. S. National Institutes of Health, could conduct this research. But research can go on for years, during which time few peo- ple will have access through the trials, so we also need whatever organizing is required to support patients and physicians who want to try passive immunotherapy before all the research is com- plete. Since plasmapheresis and transfusion of plasma are already standard medical procedures, already regulated to assure good medical practice and patient safety, the same procedures already in use should be available in this case. Physicians clearly have the right to use a standard drug or procedure for a new treatment purpose. Patients who need this treatment, espe- cially those who have no other options, should have access to it without waiting the many years required for approval of new drugs. Results of the treatment should be closely monitored, so that others can benefit from the experience as it becomes avail- able. Unfortunately the FDA seems unlikely to allow their "treat- ment IND" -- the rules announced over a year ago to make early treatments more available for serious or life-threatening diseases -- to be used for passive immunotherapy. (See "Beyond an Unreasonable Doubt: Comments on Drug-Approval Delays", below.) All options will need to be explored. References American Foundation for AIDS Research. AIDS/HIV Experimental Treatment Directory. Passive immunotherapy section, August 1988 and later. Forster SM and others. Decline of Anti-p24 Antibody Precedes Antigenemia as Correlate of Prognosis in HIV-1 Infection. AIDS (England), volume 1 number 4, pages 235-240, December 1987. Jackson GG and others. Passive Immunoneutralization of Human Immunodeficiency Virus in Patients with Advanced AIDS". The Lan- cet, September 17, 1988, pages 647-652. ***** Ampligen: Study Stopped After Poor Results An article in The New York Times October 14 confirmed rumors that had been circulating for weeks -- that ampligen was not proving effective in the current double-blind trials. After 20 patients in that study progressed to AIDS, the code was broken for those 20. Twelve of them were taking ampligen, compared to eight who were taking the placebo -- indicating that ampligen was not stopping the progression to AIDS. According to a phone call from one patient in the study, a higher-dose arm of the trial might still be continued. Ampligen had been considered a very promising treatment after an earlier study, published in June 1987, reported good results in 10 patients with AIDS, ARC, or lymphadenopathy -- especially reductions in viral cultures or other measures of viral activity. That study did not have enough patients to look for prevention of progression to AIDS. Apparently no one knows why the two studies of the same drug produced such different results. Finding out why might help prevent similar errors in the future. ***** FDA Issues Rules to Speed Drug Testing On October 19 the U. S. Food and Drug Administration announced new regulations to speed the development and commercial release of some drugs. Initial reaction by AIDS organizations has been mostly negative (see The New York Times, October 20, page 1). Project Inform expressed limited support. The rules essentially codify what was already done with AZT. They ask drug companies to work more closely with the FDA to design an expanded phase II (efficacy study), after which drugs could be released without going through a phase III (larger effi- cacy study). But there are no commitments to use the new pro- cedures in any particular situations; and some have questioned whether the FDA has enough money or staff to handle accelerated approvals. These rules were adopted after months of bitter infighting behind the scenes. Powerful FDA officials who never wanted this reform may try to sabotage it. The previous "treatment IND" (now called "treatment proto- col") remains as before. In theory those rules permit the early release of treatment for life-threatening or severely debilitat- ing illness; in practice they have almost never been used since they were announced over a year ago. The current new rules do not change the real intentions and operations of the agency concerning early release of drugs before full commercial approval. The FDA still adamantly refuses to allow early release through the treatment protocol (treatment IND) unless it believes that the data supports approval for full commercial marketing and only paperwork remains. The treatment protocol can be used only to get the drug to patients during the time of this considerable paperwork; it is only a steppingstone toward commercial release. The FDA sees no drug as eligible for commercial release (and therefore none eligible for a treatment protocol) at this time. For reasons outlined in "Beyond an Unreasonable Doubt", below, we believe that this new FDA ruling will do nothing for AIDS in the foreseeable future, probably nothing for at least two years. Yet it may be an important long-range step toward improv- ing U. S. drug regulation. Martin Delaney, co-founder of Project Inform, called the rules "only a small step, not the whole solution to the problems we have been addressing for the last three years... Nevertheless, they stake out new philosophical ground for the agency, ack- nowledging for the first time that drugs must be evaluated flexi- bly, that the rules should be different when a life-threatening illness is involved, and that approval should be based on a risk-benefit analysis rather than rigid, standard rules." For a copy of the new rule, which will appear in the Code of Federal Regulations, 21 CFR 312 as a new Subpart E, "Drugs Intended to Treat Life-Threatening and Severely-Debilitating Illnesses", send a self-addressed stamped envelope to AIDS Treat- ment News, P. O. Box 411256, San Francisco, CA 94141. Ask for the FDA rule. ***** Beyond an Unreasonable Doubt: Comments on Drug-Approval Delays The new FDA rules are unlikely to make any practical differ- ence for two years or more, because they concern procedures for expanded "phase II" trials which have not yet even been designed, let alone recruited for, conducted, and analyzed. The new docu- ment fails to address the most important FDA issue for AIDS: allowing access to treatments which have been proved safe (or which have known and acceptable risks), and which do show good, credible evidence that they may be effective, but which do not have enough scientific data yet to justify full release for com- mercialization. (Such commercialization includes glossy ads in medical journals, sales forces and promotional campaigns target- ing doctors who do not have time to read the literature and make their own evaluations, doctors using the new drug for non- approved and non-emergency purposes as well as approved or emer- gency ones, etc. It is understandable that the FDA insists on very thorough proof first.) Why does the FDA refuse to allow a separate standard and procedure for early, less commercial, conditional release in an emergency? The agency purported to do this with its "treatment IND" announced over a year ago. But the treatment IND has almost never been used; and FDA officials do not conceal the fact that they never intended to let the treatment IND employ any lesser standard of proof than required for full commercialization. The treatment IND (called "treatment protocol" in the new regula- tions) was never intended to allow early release until the FDA already knows, based on its access to proprietary data concealed from the public, that the drug will qualify for full commercial release, and only paperwork remains to complete the approval. Why does the FDA ask patients to wait years for treatments for life-threatening illnesses when it is known the treatments are safe, and that they probably do work (though none yet is a cure for AIDS)? Why not let patients and their physicians make their own decisions based on the specifics of each case -- specifics the FDA cannot possibly respond to, as it cannot know them in advance? Why does the FDA refuse to do in reality what it pretended to do when it announced the treatment IND, over a year ago? We can only guess at the motives of the agency. But one particular guess clarifies mountains of confusion about FDA pol- icy. This explanation also reveals why the treatment IND failed (why it never represented the real intent of the staff), and why the FDA strongly discourages compassionate use and punishes com- panies which make their drugs widely available that way (such as Syntex with ganciclovir, also called DHPG). For if early emergency release required any less data than full commercialization, then some drugs allowed into emergency use would later fail to meet the criteria for general marketing. Then what would happen to the hundreds, maybe thousands of people who were using the drug and were convinced, wrongly or rightly, that it was helping them stay alive? (Even drugs rejected for commercial marketing can in fact save the lives of some people, even if not enough people for statistical proof.) If the FDA or the manufacturer were to cut these people off, there would be tremendous protests -- much more than if the drug had been denied in the first place, before the patients had any personal experience with it. In politics there is a saying that people don't fight to get, they fight to keep. Those who have used a drug and found that it helped them will protest much more forcefully if it is taken away, than if they had only read about the drug in a newspaper -- or not heard about it at all. But if the FDA or the manufacturer did not cut the patients off, then the drug companies would need to maintain manufacturing (and the FDA to maintain regulation of good manufacturing prac- tices, etc.) indefinitely for a dead-end drug never expected to be approved. For how long -- until the last person no longer wanted it? The drug would stay in limbo -- in use, but going nowhere. By simply holding up emergency release under the treatment protocol (treatment IND) until it is clear that a drug will even- tually get full commercial approval and awaits only the paper- work, the FDA prevents in advance the awkward dilemma of ever having to take a drug back -- or to allow the creation of a new class of drugs never to be approved but officially released and permanently in use anyway. Thousands of lives are being lost and will be lost to this policy of refusing to allow early treatment release in emergen- cies, without the full proof required for commercialization. This policy gravely delays the drugs which are good enough to eventually be approved, and it impedes research by preventing physicians from developing practical knowledge early. Treatments affected include the passive immunotherapy dis- cussed above, imuthiol, fluconazole (which might get a treatment IND as it may already meet standards for marketing), trimetrexate (which has a treatment IND, the only one for an AIDS drug, but is highly restricted and cannot be tried for other infections such as cryptosporidiosis), aerosol pentamidine (available anyway without official sanction), dextran sulfate (available anyway), and colony stimulating factor (not usually available, and a seri- ous problem for patients and physicians who cannot obtain it). Other treatments which might soon be ready for early release, but which probably will not be allowed due to the FDA policy dis- cussed above, include CD4, ddC, and ddI. This policy grossly mis-serves the public but still will be hard to change. For a triple alliance composed of drug com- panies, the FDA, and good-government, consumer-protection advo- cates, who usually have different interests which roughly balance each other, are on the same side of this issue: * Drug companies want full commercial approval. They do not want the profitless bother and liability of early release, which may lead to dead-end drugs which will never be approved, but which they cannot discontinue without serious public-relations cost. And companies big enough to afford the $80 million to $120 million bill for each new drug approval do not want to make open- ings for smaller competitors. (The code words for this corporate wing of the triple alliance are that small "fly by night" com- panies could profit by "quack" remedies, if allowed earlier, easier emergency release of their products.) * The FDA fears bad publicity, and greatly fears any independent public movement for a drug, beyond its control. Early release invites just such a movement, if the FDA later rejects the drug. In other words, the agency could lose control if allowed early release before it was clear that the drug would eventually be approved for marketing. So it blocks emergency access, often secretly by pressure behind the scenes, with catas- trophic consequences for patients -- not for their benefit but for its own. (The code words are "greatest good for the greatest number", to justify policies clearly against patients' interests.) * Consumer-protection advocates have fought step by step for decades to control dangerous and unscrupulous drug-company prac- tices. The fight over early emergency release exposes a basic flaw in our whole system of drug development and regulation. Regulation advocates fear a weakening of the walls they have so laboriously built up. (The code words are that "standards" of "science" should not be "weakened" because of the AIDS emer- gency.) Also, the problem will be hard to fix because it is hard to imagine any graceful solution. Any emergency release based on a standard of evidence short of that for full marketing approval will by definition either create awkward take-backs, or create an indefinite limbo for dead-end drugs. But thousands die unneces- sarily because patients are denied access to safe and effective treatments pending full justification for commercialization, and because this system greatly delays research by requiring years of red tape to finance, set up, and run elaborate studies to get academic answers when physicians could otherwise get practical answers in weeks. The standard now in use could be called proof beyond unrea- sonable doubt. Any possibility, no matter how farfetched, of erroneously approving a drug which does not work must be ruled out. Society may well want this meticulous standard for routine medical improvements. But it is deadly in an emergency. If AIDS had affected all people equally and not been concentrated in unpopular groups, it is hard to believe that no accommodation would yet have been made. The current policy of withholding emergency treatments until they meet standards for full-scale commercial release amounts to genocide by business as usual. The new FDA rules try to reduce the pressure for emergency release by promising to speed final commercial release for life- threatening or seriously disabling illnesses. But these rules apply to studies yet to be devised, so they will not help anyone with AIDS in the foreseeable future. The problem today is the same as it has always been. Agen- cies, corporations, and professionals have been in business for decades and have negotiated arrangements in their own interests. Patients, unwilling newcomers to the world of medical policy, have had vastly less influence. That is why U. S. drug-approval policy sacrifices thousands of lives for regulatory and corporate convenience. The public usually avoids the complex and rarified world of regulation. But AIDS is different from other regulatory issues because at least a million U. S. citizens have a life-or-death interest in FDA decisions. Along with the giant corporations, the bureaucrats, and the good-government advocates who were formed in an earlier era, these citizens must and will be heard. ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display